We recently posted on the nocebo response; the better known entity is placebo. The placebo response is fascinating, as it is a very real response. Our studies generally involve testing the effects of a drug, or procedure, versus placebo. For instance, if we have a new pain drug, we would enroll 60 people in a study, and have 1/2 try the real drug, and 1/2 would get the sugar type “placebo” pill; neither they nor the doctor would know which is which(hence, “double-blind study; if the doctor knows, and the patient does not know, it is “single-blind”). In many studies, the patients would then, after getting one or the other(real drug vs. placebo), “cross-over” and take whichever one they did not recieve(so, in many trials, patients would try both placebo and the real drug).
The placebo effect is very real; if someone takes a placebo sugar pill, and believes it is a pain pill, they often get this “rush” of endogenous(from their own body) opioid into the middle of their brain(technically, the PAG around the CSF, or spinal fluid, in the brainstem). This internal opioid works for pain, and the person does not feel pain. However, this effect often goes away over time(weeks to a month or so), so the placebo usually(but not always) stops working. Many studies have turned out to be negative, where the real “active” drug does not work much better than placebo, because the placebo response rate is very high. This has happened in a # of Botox for chronic migraine studies, where Botox did work, but the placebo rate was so high(40 to 50% of people responded to placebo), that it could not be demonstrated that Botox was more effective than placebo. The “therapeutic gain” in studies is essentially how much better the drug is than the placebo; if 50% respond to placebo, and 58% to active drug, the therapeutic gain is only 8%. Therefore, even tho 58% of the patients may have responded, due to the high placebo rate, the gain is only 8%, and the study will be deemed negative; not because the drug did not work, but because of the high placebo rate.
Placebo is a huge area; there are many issues. Many articles and several books have been written on this subject. Some of the issues involve: 1.the differences in placebo response rates between various cultures and continents(North American placebo rates tend to differ from European, for some reason), 2. dealing with kids or adolescents is much different than with adults, as far as placebo, a number of earlier migraine studies in high school kids came out negative because of placebo, 3. gender differences, 4. in some studies we use an “active placebo”, not exactly a sugar pill, but rather one that has some activity, so as to mimic the effects of the active drug being tested, 5. how the researcher should present the placebo, what words to use when presenting the drug to the patient, 6. how to make the placebo seem like the “real” drug, 7. side effects: in headache trials, 10 to 15% of people have significant, or at least annoying, side effects to placebo, and many pateints drop out of the studies due to side effects from the placebo(or, perceived side effects)…….and, many many more issues.
So, I find the placebo response to be a fascinating topic, with many areas to explore. It is a real physiologic response, with complex mechanisms, and we are just beginning to realize all of the true physiologic effects that occur with placebo.
For more info, you can google placebo, or go on NIH PubMed for articles, and there are several books out.
